Synthesis and evaluation of novel heterocyclic compounds as anticancer agents

There is a clear need for anti-cancer therapies that have effective cytotoxic efficiency andmarginal toxicity, preferably zero. For this goal, researchers have been persevering todevelop new drugs from natural resources. Among them are agents that target tubulin,which is a protein found in all eukaryotic cells. This protein is an essential component formitosis and has several different binding sites at which a variety of chemically differentagents interact. These binding sites include the colchicine, vinca alkaloids, rhizoxin/maytansine and tubulin sulfhydryl binding sites. Combretastatin A-4 is one of the mostpotent natural products targeting tubulin and prevents microtubule polymerisation thatleads to mitosis arrest and apoptosis in endothelial cells. Moreover, it can cause selectivevascular shutdown for the tumour cell and results in haemorrhagic necrosis for the solidtumour. However, cis-combretastatin is more active than the trans isomer. Toxicity tonormal cells has limited its use as an effective chemotherapy. Another problem with thisisomer is the in vivo instability, by which the unstable cis isomer converts to the morestable inactive trans-isomer.To overcome this problem, many combretastatin analogues have been synthesized andevaluated in terms of antimitotic and cytotoxic activity as well as toxicity. 6-(4-Methoxy-3-nitrophenyl)-5-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3(2H)-one, and series of : 2,3-diaryl-3H-imidazo[4,5-b]pyridine, and N-((2-arylamino)pyridine)benzenesulphonamidederivatives, which related to E7010, have been synthesised as possible active analoguesof combretastatin A-4.These heterocyclic analogues have been characterized and examined for their ability tosuppress the growth of A549, U-2 OS, BEAS-2B, Saos-2, Hep-G2, and A204 mammaliancell lines by MTT assay, and flowcytometry. 3-Hydroxy-4-methoxy-N-(2-((3,4,5-trimethoxybenzyl)amino)pyridin-3-yl)benzenesulfonamide, was the most potentcompound evaluated with an IC50 of 1.15µM in the Carcinoma A549 cell line. It is alsocaused cells to hold up in the G2/M phase of the cell cycle (37.34 %).

Level dc:type.qualificationlevel

Doctoral (Level 8)

Year dc:date.issued

2020

Author dc:creator

• Mal ullah, AARA

Language dc:language

en

Identifier

oai:salford-repository.worktribe.com:1353959

OAI identifier oai:identifier

oai:salford-repository.worktribe.com:1353959